Implantable device for controlled release of drug

ABSTRACT

Implantable medical devices are provided for controlled release of drugs. In one embodiment, the device comprises a support structure; two or more discrete reservoirs provided in spaced positions across at least one surface of the support structure; and a release system loaded in each of the reservoirs, the release system including drug molecules dispersed in a degradable matrix material, wherein release of the drug molecules from the reservoir is controlled by in vivo disintegration of the matrix material. In another embodiment, the device comprises a support structure; two or more discrete reservoirs provided in spaced positions across at least one surface of the support structure; and a release system loaded in each of the reservoirs, the release system including drug molecules dispersed in a non-degradable matrix material, wherein release of the drug molecules from the reservoir is controlled by in vivo diffusion of the drug molecules from the matrix material.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This is a continuation of U.S. application Ser. No. 09/665,303,filed Sep. 19, 2000, which is a continuation-in-part of U.S. applicationSer. No. 09/022,322, filed Feb. 11, 1998, now U.S. Pat. No. 6,123,861,which is a continuation-in-part of U.S. application Ser. No. 08/675,375,filed Jul. 2, 1996, now U.S. Pat. No. 5,797,898. These applications areincorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

[0002] This invention relates to miniaturized drug delivery devices andmore particularly, to controlled time and rate release multi-welled drugdelivery devices.

[0003] Drug delivery is an important aspect of medical treatment. Theefficacy of many drugs is directly related to the way in which they areadministered. Some therapies require that the drug be repeatedlyadministered to the patient over a long period of time. This makes theselection of a proper drug delivery method problematic. Patients oftenforget, are unwilling, or are unable to take their medication. Drugdelivery also becomes problematic when the drugs are too potent forsystemic delivery. Therefore, attempts have been made to design andfabricate a delivery device which is capable of the controlled,pulsatile or continuous release of a wide variety of moleculesincluding, but not limited to, drugs and other therapeutics.

[0004] Controlled release polymeric devices have been designed toprovide drug release over a period of time via diffusion of the drug outof the polymer and/or degradation of the polymer over the desired timeperiod following administration to the patient. However, these devicesare relatively simple.

[0005] U.S. Pat. No. 5,490,962 to Cima, et al. discloses the use ofthree dimensional printing methods to make more complex devices whichprovide release over a desired time frame, of one or more drugs.Although the general procedure for making a complex device is described,specific designs are not detailed.

[0006] U.S. Pat. No. 4,003,379 to Ellinwood describes an implantableelectromechanically driven device that includes a flexible retractablewalled container, which receives medication from a storage area via aninlet and then dispenses the medication into the body via an outlet.U.S. Pat. No. 4,146,029 and U.S. Pat. No. 3,692,027 to Ellinwooddisclose self-powered medication systems that have programmableminiaturized dispensing means. U.S. Pat. No. 4,360,019 to Jassawalladiscloses an implantable infusion device that includes an actuatingmeans for delivery of the drug through a catheter. The actuating meansincludes a solenoid driven miniature pump. All of these devices includeminiature power-driven mechanical parts that are required to operate inthe body, i.e., they must retract, dispense, or pump. These arecomplicated and subject to breakdown. Moreover, due to complexity andsize restrictions, they are unsuitable to deliver more than a few drugsor drug mixtures at a time.

[0007] It therefore would be desirable to provide a multi-welleddelivery device that is relatively simple to use and manufacture, butwhich is dependable and capable of delivering drugs or other moleculesand can operate for weeks or years at a time. It would also be desirableto provide such a device that provides the delivery of drugs or othermolecules in a controlled manner, such as continuously or pulsatile, andwhich operates actively or passively. It would further be desirable toprovide such a device that can hold many different drugs or othermolecules of varying dosages and is small enough to be implanted.

SUMMARY OF THE INVENTION

[0008] Devices are provided for the controlled release of molecules. Thedevices include (1) a substrate comprised of two or more substrateportions bonded together, (2) at least two reservoirs in the substratecontaining the molecules for release, and (3) a reservoir cap positionedon, or within a portion of, the reservoir and over the molecules, sothat the molecules are controllably released from the device bydiffusion through or upon disintegration of the reservoir caps. In apreferred embodiment, the substrate comprises an upper substrate portionadjacent the reservoir cap and a lower substrate portion distal thereservoir cap, such that a reservoir section in the upper substrateportion is in communication with a reservoir section in the lowersubstrate portion, the two reservoir sections forming a single reservoirwhich generally is larger than that which would be provided using thesingle substrate device.

[0009] In an alternative embodiment, an internal reservoir cap isinterposed between a reservoir section of the upper substrate portionand a reservoir section of the lower substrate portion, wherein releaseof the molecules from the reservoir section in the lower substrateportion is controlled by diffusion through or disintegration of theinternal reservoir cap. The internal reservoir cap can bedisintegratable so that the two reservoir sections thereby form a singlereservoir. In this alternative embodiment, the reservoir section of thelower substrate portion can contain molecules different in quantity,type, or both quantity and type, from the molecules contained in thereservoir section of the upper substrate portion.

[0010] In a preferred embodiment, the molecule to be delivered is adrug. The drug can be provided alone or in a release system, such as abiodegradable matrix, or in any other pharmaceutically acceptablecarrier. Combinations of different drugs can be delivered in differentreservoirs or even in different reservoir sections as in the embodimentcontaining internal reservoir caps. The reservoirs can contain multipledrugs or other molecules in variable dosages.

[0011] Methods for making these microchip devices are also provided. Inpreferred embodiments, reservoirs are etched into two or more substrateportions using either chemical (wet) etching or plasma (dry) etchingtechniques well known in the field of microfabrication. Hundreds tothousands of reservoirs can be fabricated on a single substrate portionusing these techniques. SOI techniques also can be adapted to make thereservoirs. The reservoir sections of the substrate portions are alignedand then the portions are bonded together. The reservoirs, or portionsthereof, are filled either prior to or after the portions are bondedtogether.

[0012] Each of the reservoirs of a single microchip can containdifferent molecules and/or different amounts and concentrations, whichcan be released independently. The filled reservoirs can be capped withmaterials that passively disintegrate, materials that allow themolecules to diffuse passively out of the reservoir over time, ormaterials that disintegrate upon application of an electric potential.Release from an active device can be controlled by a preprogrammedmicroprocessor, remote control, or by biosensors.

BRIEF DESCRIPTION OF THE DRAWINGS

[0013]FIG. 1 depicts a typical fabrication scheme for a passive deliverydevice.

[0014]FIG. 2 depicts a typical fabrication scheme for an active deliverydevice.

[0015]FIG. 3 depicts a typical device control circuitry flowsheet.

[0016]FIG. 4 depicts a passive delivery device.

[0017]FIG. 5 depicts an active delivery device.

[0018]FIG. 6 depicts an active device including insulator overlayers.

[0019]FIGS. 7a-i are schematic views of several configurations ofpassive delivery devices.

[0020]FIGS. 8a-c are schematic views of several configurations of activedelivery devices.

[0021]FIGS. 9a-e are cross-sectional schematic views of variousembodiments of devices having substrates formed from two fabricatedsubstrate portions which have been joined together.

DETAILED DESCRIPTION OF THE INVENTION

[0022] Microchip devices have been provided which can accurately deliverdrugs and other molecules at defined rates and times according to theneeds of the patient or other experimental system. As used herein, a“microchip” is a miniaturized device fabricated using methods commonlyapplied to the manufacture of integrated circuits and MEMS(MicroElectroMechanical Systems) such as ultraviolet (UV)photolithography, reactive ion etching, and electron beam evaporation,as described, for example, by Wolf & Tauber, Silicon Processing for theVLSI Era, Volume 1—Process Technology (Lattice Press, Sunset Beach,Calif., 1986); and Jaeger, Introduction to Microelectronic Fabrication,Volume V in The Modular Series on Solid State Devices (Addison-Wesley,Reading, Mass., 1988), as well as MEMS methods that are not standard inmaking computer chips, including those described, for example, in Madou,Fundamentals of Microfabrication (CRC Press, 1997) and micromolding andmicromachining techniques known in the art. The microchips providecontrol over the rate the molecules are released as well as the time atwhich release begins. The time of release can be controlled passively oractively. The microchip fabrication procedure allows the manufacture ofdevices with primary dimensions (length of a side if square orrectangular, or diameter if circular) ranging from less than amillimeter to several centimeters. A typical device thickness is 300 μm.However, the thickness of the device can vary from approximately 10 μmto several millimeters, depending on the device's application. Totaldevice thickness and reservoir volume can also be increased by bondingor attaching additional silicon wafers or other substrate materials tothe fabricated microchip device. In general, changing the devicethickness affects the maximum number of reservoirs that may beincorporated onto a microchip and the volume of each reservoir. In vivoapplications of the device would typically require devices having aprimary dimension of 2 cm or smaller. Devices for in vivo applicationsare small enough to be swallowed or implanted using minimally invasiveprocedures. Smaller in vivo devices (on the order of a millimeter) canbe implanted using a catheter or other injectable means. Devices for invitro applications have fewer size restrictions and, if necessary, canbe made much larger than the dimension ranges for in vivo devices.

[0023] I. Device Components and Materials

[0024] Each device consists of a substrate, reservoirs, and a releasesystem containing, enclosing, or layered with the molecules to bedelivered. Devices which control the release time of the molecules mayinclude reservoir caps. Active devices may include control circuitry anda power source.

[0025] A. The Substrate

[0026] The substrate contains the etched, molded, or machined reservoirsand serves as the support for the microchip. Any material which canserve as a support, is suitable for etching, molding, or machining, andis impermeable to the molecules to be delivered and to the surroundingfluids, for example, water, blood, electrolytes or other solutions, maybe used as a substrate. Examples of substrate materials includeceramics, semiconductors, and degradable and non-degradable polymers.Biocompatibility of the substrate material is preferred, but notrequired. For in vivo applications, non-biocompatible materials may beencapsulated in a biocompatible material, such as poly(ethylene glycol)or polytetrafluoroethylene-like materials, before use. One example of astrong, non-degradable, easily etched substrate that is impermeable tothe molecules to be delivered and the surrounding fluids is silicon. Inanother embodiment, the substrate is made of a strong material thatdegrades or dissolves over a period of time into biocompatiblecomponents. This embodiment is preferred for in vivo applications wherethe device is implanted and physical removal of the device at a latertime is not feasible or recommended, for example, brain implants. Anexample of a class of strong, biocompatible materials are thepoly(anhydride-co-imides) discussed by K. E. Uhrich et al., “Synthesisand characterization of degradable poly(anhydride-co-imides)”,Macromolecules, 28:2184-93 (1995).

[0027] The substrate can be formed of only one material or can be acomposite or multi-laminate material, e.g., several layers of the sameor different substrate materials that are bonded together. Multi-portionsubstrates can include any number of layers of silicon, glasses,ceramics, semiconductors, metals, polymers, or other substratematerials. Two or more complete microchip devices also can be bondedtogether to form multi-portion substrate devices (see, e.g., FIGS.9a-e).

[0028] B. Release System

[0029] The molecules to be delivered may be inserted into the reservoirsin their pure form, as a liquid solution or gel, or they may beencapsulated within or by a release system. As used herein, “releasesystem” includes both the situation where the molecules are in pureform, as either a solid or liquid, or are in a matrix formed ofdegradable material or a material which releases incorporated moleculesby diffusion out of or disintegration of the matrix. The molecules canbe sometimes contained in a release system because the degradation,dissolution or diffusion properties of the release system provide amethod for controlling the release rate of the molecules. The moleculescan be homogeneously or heterogeneously distributed within the releasesystem. Selection of the release system is dependent on the desired rateof release of the molecules. Both non-degradable and degradable releasesystems can be used for delivery of molecules. Suitable release systemsinclude polymers and polymeric matrices, non-polymeric matrices, orinorganic and organic excipients and diluents such as, but not limitedto, calcium carbonate and sugar. Release systems may be natural orsynthetic, although synthetic release systems are preferred due to thebetter characterization of release profiles. The release system isselected based on the period over which release is desired, generally inthe range of at least three to twelve months for in vivo applications.In contrast, release times as short as a few seconds may be desirablefor some in vitro applications. In some cases, continuous (constant)release from a reservoir may be most useful. In other cases, a pulse(bulk) release from a reservoir may provide more effective results. Notethat a single pulse from one reservoir can be transformed into pulsatilerelease by using multiple reservoirs. It is also possible to incorporateseveral layers of a release system and other materials into a singlereservoir to achieve pulsatile delivery from a single reservoir.Continuous release can be achieved by incorporating a release systemthat degrades, dissolves, or allows diffusion of molecules through itover an extended period of time. In addition, continuous release can besimulated by releasing several pulses of molecules in quick succession.

[0030] The release system material can be selected so that molecules ofvarious molecular weights are released from a reservoir by diffusion outor through the material or degradation of the material. Biodegradablepolymers, bioerodible hydrogels, and protein delivery systems arepreferred for release of molecules by diffusion, degradation, ordissolution. In general, these materials degrade or dissolve either byenzymatic hydrolysis or exposure to water in vivo or in vitro, or bysurface or bulk erosion. Representative synthetic, biodegradablepolymers include: poly(amides) such as poly(amino acids) andpoly(peptides); poly(esters) such as poly(lactic acid), poly(glycolicacid), poly(lactic-co-glycolic acid), and poly(caprolactone);poly(anhydrides); poly(orthoesters); poly(carbonates); and chemicalderivatives thereof (substitutions, additions of chemical groups, forexample, alkyl, alkylene, hydroxylations, oxidations, and othermodifications routinely made by those skilled in the art), copolymersand mixtures thereof. Representative synthetic, non-degradable polymersinclude: poly(ethers) such as poly(ethylene oxide), poly(ethyleneglycol), and poly(tetramethylene oxide); vinyl polymers—poly(acrylates)and poly(methacrylates) such as methyl, ethyl, other alkyl, hydroxyethylmethacrylate, acrylic and methacrylic acids, and others such aspoly(vinyl alcohol), poly(vinyl pyrolidone), and poly(vinyl acetate);poly(urethanes); cellulose and its derivatives such as alkyl,hydroxyalkyl, ethers, esters, nitrocellulose, and various celluloseacetates; poly(siloxanes); and any chemical derivatives thereof(substitutions, additions of chemical groups, for example, alkyl,alkylene, hydroxylations, oxidations, and other modifications routinelymade by those skilled in the art), copolymers and mixtures thereof.

[0031] C. Molecules to Be Released

[0032] Any natural or synthetic, organic or inorganic molecule ormixture thereof can be delivered. In one embodiment, the microchip isused to deliver drugs systemically to a patient in need thereof. Inanother embodiment, the construction and placement of the microchip in apatient enables the localized release of drugs that may be too potentfor systemic delivery. As used herein, drugs are organic or inorganicmolecules, including proteins, nucleic acids, polysaccharides andsynthetic organic molecules, having a bioactive effect, for example,anaesthetics, vaccines, chemotherapeutic agents, hormones, metabolites,sugars, immunomodulators, antioxidants, ion channel regulators, andantibiotics. The drugs can be in the form of a single drug or drugmixtures and can include pharmaceutically acceptable carriers. Inanother embodiment, molecules are released in vitro in any system wherethe controlled release of a small (milligram to nanogram) amount of oneor more molecules is required, for example, in the fields of analyticchemistry or medical diagnostics. Molecules can be effective as pHbuffering agents, diagnostic agents, and reagents in complex reactionssuch as the polymerase chain reaction or other nucleic acidamplification procedures.

[0033] D. Reservoir Caps

[0034] In the passive timed release drug delivery devices, the reservoircaps are formed from a material that degrades or dissolves over time, ordoes not degrade or dissolve but is permeable to the molecules to bedelivered. These materials are preferably polymeric materials. Materialscan be selected for use as reservoir caps to give a variety ofdegradation rates or dissolution rates or permeabilities to enable therelease of molecules from different reservoirs at different times and,in some cases, different rates. To obtain different release times(amounts of release time delay), caps can be formed of differentpolymers, the same polymer with different degrees of crosslinking, or aUV polymerizable polymer. In the latter case, varying the exposure ofthis polymer to UV light results in varying degrees of crosslinking andgives the cap material different diffusion properties or degradation ordissolution rates. Another way to obtain different release times is byusing one polymer, but varying the thickness of that polymer. Thickerfilms of some polymers result in delayed release time. Any combinationof polymer, degree of crosslinking, or polymer thickness can be modifiedto obtain a specific release time or rate. In one embodiment, therelease system containing the molecules to be delivered is covered by adegradable cap material which is nearly impermeable to the molecules.The time of release of the molecules from the reservoir will be limitedby the time necessary for the cap material to degrade or dissolve. Inanother embodiment, the cap material is non-degradable and is permeableto the molecules to be delivered. The physical properties of thematerial used, its degree of crosslinking, and its thickness willdetermine the time necessary for the molecules to diffuse through thecap material. If diffusion out of the release system is limiting, thecap material delays the onset of release. If diffusion through the capmaterial is limiting, the cap material determines the release rate ofthe molecules in addition to delaying the onset of release.

[0035] II. Methods of Making the Microchip Devices

[0036] A. Fabrication of the Reservoirs

[0037] Devices are manufactured using methods known to those skilled inthe art, reviewed, for example, by Wolf et al. (1986), Jaeger (1988),and Madou, Fundamentals of Microfabrication (CRC Press, 1997).

[0038] In a preferred method of microchip manufacture, depicted in FIGS.1 and 2, passive and active devices, respectively, fabrication begins bydepositing and photolithographically patterning a material, typically aninsulating or dielectric material, onto the substrate to serve as anetch mask during reservoir etching. Typical insulating materials for useas a mask include silicon nitride, silicon dioxide, and some polymers,such as polyimide. In a preferred embodiment, a thin film (approximately1000-3000 Å) of low stress, silicon-rich nitride is deposited on bothsides of a silicon wafer 30/300 in a Vertical Tube Reactor (VTR).Alternatively, a stoichiometric, polycrystalline silicon nitride (Si₃N₄)can be deposited by Low Pressure Chemical Vapor Deposition (LPCVD), oramorphous silicon nitride can be deposited by Plasma Enhanced ChemicalVapor Deposition (PECVD). Reservoirs are patterned into the siliconnitride film on one side of the wafer 32/320 by ultravioletphotolithography and either plasma etching or a chemical etch consistingof hot phosphoric acid or buffered hydrofluoric acid. The patternedsilicon nitride serves as an etch mask for the chemical etching of theexposed silicon 34/340 by a concentrated potassium hydroxide solution(approximately 20-40% KOH by weight at a temperature of 75-90° C.).Alternatively, the reservoirs can be etched into the substrate by dryetching techniques such as reactive ion etching or ion beam etching.These techniques are commonly used in the fabrication of microelectronicdevices, as reviewed, for example, by Wolf et al. (1986) and Jaeger(1988). Use of these microfabrication techniques allows theincorporation of hundreds to thousands of reservoirs on a singlemicrochip. The spacing between each reservoir depends on its particularapplication and whether the device is a passive or active device. In apassive device, the reservoirs may be less than one micron apart. In anactive device, the distance between the reservoirs may be slightlylarger (between approximately 1 and 10 μm) due to the space occupied bythe electrodes on or near each reservoir. Reservoirs can be made innearly any shape and depth, and need not pass completely through thesubstrate. In a preferred embodiment, the reservoirs are etched into a(100) oriented, silicon substrate by potassium hydroxide, in the shapeof a square pyramid having side walls sloped at 54°, and pass completelythrough the substrate (approximately 300 μm) to the silicon nitride filmon the other side of the substrate, forming a silicon nitride membrane.(Here, the silicon nitride film serves as a potassium hydroxide etchstop.) The pyramidal shape allows easy filling of the reservoirs throughthe large opening of the reservoir (approximately 500 μm by 500 μm) onthe patterned side of the substrate, release through the small openingof the reservoir (approximately 50 μm by 50 μm) on the other side of thesubstrate, and provides a large cavity inside the device for storing thedrugs or other molecules to be delivered.

[0039] Multi-portion substrate devices can be formed simply by makingtwo or more individual substrate portions and then bonding them to oneanother with the matching openings of the reservoir sections aligned.There are two main types of bonds that can be formed between substrateportions. The first are atomic-scale or molecular-scale bonds. Thesetypes of bonds usually involve the interpenetration, intermixing, orinterdiffusion of atoms or molecules of one or more of the substrates atthe interface between the substrate materials. A preferred method ofthis type of substrate bonding for use primarily with silicon or glasssubstrates involves using heat and/or electric voltages to enable theinterdiffusion of material between the two substrates, causing amolecular-scale bond to form at the interface between silicon, glass,and other similar materials. This anodic bonding process is well knownin the art. Another embodiment of this type of bonding involves meltingand re-solidification of the top layer of one or both substrates at aninterface between two or more substrate portions. The melted materialintermixes, and upon solidification, a strong bond is formed between thesubstrate portions. In one embodiment, this melting andre-solidification can be caused by the brief application of a solvent(for example, methylene chloride) to the substrate, e.g., PLEXIGLAS™ (anacrylic) or LEXAN™ (polycarbonate). The second type of bonding methodsinvolves using a material other than the substrate material to form thebond. A preferred embodiment of this type of bonding includes the use ofchemical adhesives, epoxies, and cements. An embodiment that could beused with UV transparent substrate materials would involve UV curableepoxy. The UV curable epoxy would be spread between the two substrateportions using a method such as spin coating, the reservoirs would bealigned, and a UV light source would be used to cross-link (i.e. cure)the epoxy and bond the substrates together.

[0040] Alternatively, reservoirs also can be formed usingsilicon-on-insulator (SOI) techniques, such as is described in S.Renard, “Industrial MEMS on SOI,” J. Micromech. Microeng. 10:245-249(2000). SOI methods can be usefully adapted to form reservoirs havingcomplex reservoir shapes, for example, as shown in FIGS. 9b, 9 c, and 9e. SOI wafers behave essentially as two substrate portions that havebeen bonded on an atomic or molecular-scale before any reservoirs havebeen etched into either portion. SOI substrates easily allow thereservoirs (or reservoir sections) on either side of the insulator layerto be etched independently, enabling the reservoirs on either side ofthe insulator layer to have different shapes. The reservoir (portions)on either side of the insulator layer then can be connected to form asingle reservoir having a complex geometry by removing the insulatorlayer between the two reservoirs using methods such as reactive ionetching, laser, ultrasound, or wet chemical etching.

[0041] B. Fabrication of Passive Timed Release Reservoir Caps

[0042] In FIG. 1, the steps represented by 36 a, 38 a, and 40 a, areconducted using ink jet or microinjection, while represented by 36 b, 38b, and 40 b, are conducted using spin coating. In the fabrication ofpassive timed release microchips, the reservoir cap material is injectedwith a micro-syringe 36 a, printed with an inkjet printer cartridge, orspin coated 36 b into a reservoir having the thin membrane of insulatingmask material still present over the small opening of the reservoir. Ifinjection or inkjet printing methods are used, cap formation is completeafter the material is injected or printed into the reservoir 38 a anddoes not require further processing. If spin coating is used, the capmaterial is planarized by multiple spin coatings 36 b. The surface ofthe film is then etched by a plasma, an ion beam, or chemical etchantuntil the desired cap thickness is obtained 38 b. In a preferredembodiment, the insulating material used is silicon nitride and the capmaterial is printed into the reservoir with an inkjet cartridge filledwith a solution or suspension of the cap material.

[0043] Reservoir caps control the time at which molecules are releasedfrom the reservoirs. Each reservoir cap can be of a different thicknessor have different physical properties to vary the time at which eachrelease system containing the molecules is exposed to the surroundingfluids. Injection, inkjet printing, and spin coating are the preferredmethods of reservoir filling and any of these methods may be used tofill reservoirs, regardless of the reservoir's shape or size. However,injection and inkjet printing are the preferred methods of filling deep(>100 μm) reservoirs or reservoirs with large openings (>100 μm). Forexample, to obtain different cap thicknesses using injection or inkjetprinting, different amounts of cap material are injected or printeddirectly into each individual reservoir. Spin coating is the preferredmethod of filling shallow (<10 μm) reservoirs, reservoirs that do notpass completely through the substrate, or reservoirs with small (<100μm) openings. Variation in cap thickness or material by spin coating canbe achieved by a repeated, step-wise process of spin coating, maskingselected reservoirs, and etching. For example, to vary cap thicknesswith spin coating, the cap material is spin coated over the entiresubstrate. Spin coating is repeated, if necessary, until the material isnearly planarized. A mask material such as photoresist is patterned tocover the cap material in all the reservoirs except one. Plasma, ionbeam, or chemical etchants are used to etch the cap material in theexposed reservoir to the desired thickness. The photoresist is thenremoved from the substrate. The process is repeated as a new layer ofphotoresist is deposited and patterned to cover the cap material in allthe reservoirs except one (the exposed reservoir is not the same onealready etched to its desired thickness). Etching of the exposed capmaterial in this reservoir continues until the desired cap thickness isobtained. This process of depositing and patterning a mask material suchas photoresist, etching, and mask removal can be repeated until eachreservoir has its own unique cap thickness. The techniques, UVphotolithography, plasma or ion beam etching, etc., are well known tothose skilled in the field of microfabrication.

[0044] Although injection, inkjet printing and spin coating are thepreferred methods of cap fabrication, it is understood that eachreservoir can be capped individually by capillary action, by pulling orpushing the material into the reservoir using a vacuum or other pressuregradient, by melting the material into the reservoir, by centrifugationand related processes, by manually packing solids into the reservoir, orby any combination of these or similar reservoir filling techniques.

[0045] Once a cap fabrication method is selected, additional methods forcontrolling the time of release of molecules from a reservoir can beutilized, for example, including either UV polymerizable polymers or thelayering of release system and cap materials. In the first embodiment,where the reservoir caps are made of either an injected, inkjet printedor spin coated UV polymerizable polymer, each cap can be exposed to adifferent intensity of UV light to give varying degrees of crosslinkingand therefore, different degradation or dissolution rates for degradablecaps or different permeabilities to the molecules for non-degradablecaps. Second, layers of cap material, both degradable andnon-degradable, can be inserted between layers of the release systemcontaining the molecules to be delivered by injection, inkjet printing,spin coating, or selective crosslinking. These and other similar methodsallow complex release profiles (e.g., pulsatile delivery at irregulartime intervals) to be achieved from a single reservoir.

[0046] If desired, a passive timed release device can be fabricatedwithout reservoir caps. The rate of release of the molecules is thussolely controlled by the physical and material properties of the releasesystem containing the molecule to be delivered.

[0047] Several possible configurations for passive delivery devices areshown in FIG. 7.

[0048] C. Fabrication of Active Timed Release Reservoir Caps

[0049] In a preferred embodiment, photoresist is patterned in the formof electrodes on the surface of the substrate having the reservoirscovered by the thin membrane of insulating or dielectric material. Thephotoresist is developed such that the area directly over the coveredopening of the reservoir is left uncovered by photoresist and is in theshape of an anode. A thin film of conductive material capable ofdissolving into solution or forming soluble ions or oxidation compoundsupon the application of an electric potential is deposited over theentire surface using deposition techniques such as chemical vapordeposition, electron or ion beam evaporation, sputtering, spin coating,and other techniques known in the art. Exemplary materials includemetals such as copper, gold, silver, and zinc and some polymers, asdisclosed by Kwon et al. (1991) and Bae et al. (1994). After filmdeposition, the photoresist is stripped from the substrate. This removesthe deposited film, except in those areas not covered by photoresist(lift-off technique). This leaves conducting material on the surface ofthe substrate in the form of electrodes 360. An alternative methodinvolves depositing the conductive material over the entire surface ofthe device, patterning photoresist on top of the conductive film usingUV or infrared (IR) photolithography, so that the photoresist lies overthe reservoirs in the shape of anodes, and etching the unmaskedconductive material using plasma, ion beam, or chemical etchingtechniques. The photoresist is then stripped, leaving conductive filmanodes covering the reservoirs. Typical film thicknesses of theconductive material may range from 0.05 to several microns. The anodeserves as the reservoir cap and the placement of the cathodes on thedevice is dependent upon the device's application and method of electricpotential control.

[0050] An insulating or dielectric material such as silicon oxide(SiO_(X)) or silicon nitride (SiN_(X)) is deposited over the entiresurface of the device by methods such as chemical vapor deposition(CVD), electron or ion beam evaporation, sputtering, or spin coating.Photoresist is patterned on top of the dielectric to protect it frometching except on the cathodes and the portions of the anodes directlyover each reservoir 380. The dielectric material can be etched byplasma, ion beam, or chemical etching techniques. The purpose of thisfilm is to protect the electrodes from corrosion, degradation, ordissolution in all areas where electrode film removal is not necessaryfor release.

[0051] The electrodes are positioned in such a way that when an electricpotential is applied between an anode and a cathode, the unprotected(not covered by dielectric) portion of the anode reservoir cap oxidizesto form soluble compounds or ions that dissolves into solution, exposingthe release system containing the molecules to the surrounding fluids.The molecules are released from the reservoir at a rate dependent uponthe degradation or dissolution rate of a degradable release system orthe rate of diffusion of the molecules out of or through anon-degradable release system.

[0052] Several possible configurations for active delivery devices areshown in FIG. 8.

[0053] D. Removal of the Insulator Membrane (Reservoir Etch Stop)

[0054] The thin membrane of insulating or dielectric material coveringthe reservoir used as a mask and an etch stop during reservoirfabrication must be removed from the active timed release device beforefilling reservoir 400 and from the passive timed release device (if thereservoir extends completely through the substrate) after fillingreservoir 44. The membrane may be removed in two ways. First, themembrane can be removed by an ion beam or reactive ion plasma. In apreferred embodiment, the silicon nitride used as the insulatingmaterial can be removed by a reactive ion plasma composed of oxygen andfluorine containing gases such as CHF₃, CF₄, or SF₆. Second, themembrane can be removed by chemical etching. For example, bufferedhydrofluoric acid (BHF or BOE) can be used to etch silicon dioxide andhot phosphoric acid can be used to etch silicon nitride.

[0055] E. Reservoir Filling

[0056] The release system containing the molecules for delivery isinserted into the large opening of the reservoir by injection, inkjetprinting or spin coating 40 a/40 b/400. Each reservoir can contain adifferent molecule and dosage. Similarly, the release kinetics of themolecule in each reservoir can be varied by the choice of the releasesystem and cap materials. In addition, the mixing or layering of releasesystem and cap materials in each reservoir can be used to tailor therelease kinetics to the needs of a particular application.

[0057] The distribution over the microchip of reservoirs filled with therelease system containing the molecules to be delivered can varydepending on the medical needs of the patient or other requirements ofthe system. For applications in drug delivery, for example, the drugs ineach of the rows can differ from each other. One row may contain ahormone and another row may contain a metabolite. Also, the releasesystem can differ within each row to release a drug at a high rate fromone reservoir and a slow rate from another reservoir. The dosages canalso vary within each row. For those devices having deep (>10 μm)reservoirs or reservoirs with large (>100 μm) openings, differences inreservoir loading can be achieved by injection or inkjet printing ofdifferent amounts of material directly into each reservoir. Variationbetween reservoirs is achieved in devices having shallow (<10 μm)reservoirs, reservoirs that do not pass completely through thesubstrate, or reservoirs with small (<100 μm) openings by a repeated,step-wise process of masking selected reservoirs, spin coating, andetching, as described above regarding the fabrication by spin coating ofpassive timed release reservoir caps. Preferably, the release system andmolecules to be delivered are mixed before application to thereservoirs. Although injection, inkjet printing and spin coating are thepreferred methods of filling reservoirs, it is understood that eachreservoir can be filled individually by capillary action, by pulling orpushing the material into the reservoir using a vacuum or other pressuregradient, by melting the material into the reservoir, by centrifugationand related processes, by manually packing solids into the reservoir, orby any combination of these or similar reservoir filling techniques.

[0058] In preferred embodiments of both active and passive releasedevices, the reservoir openings used for filling (i.e., the openingsopposite the reservoir cap end) are sealed following reservoir filling,using any of a variety of techniques known in the art. For example,sealing can be provided by bonding a rigid backing plate or a thinflexible film across the opening. Alternatively, the opening can besealed by applying a fluid material, e.g., an adhesive, which plugs theopening and hardens to form a seal. In another embodiment, a secondsubstrate portion, e.g., of a second device, can be bonded across thereservoirs openings, as shown in FIG. 9.

[0059] F. Device Packaging, Control Circuitry, and Power Source

[0060] The openings through which the reservoirs of passive and activedevices are filled are sealed by wafer bonding or with a waterproofepoxy or other appropriate material impervious to the surrounding fluids44/440. For in vitro applications, the entire unit, except for the faceof the device containing the reservoirs and electrodes, is encased in amaterial appropriate for the system. For in vivo applications, the unitis preferably encapsulated in a biocompatible material such aspoly(ethylene glycol) or polytetrafluoroethylene.

[0061] The mechanism for release of molecules by the active timedrelease device does not depend on multiple parts fitted or gluedtogether which must retract or dislodge. Control of the time of releaseof each reservoir can be achieved by a preprogrammed microprocessor, byremote control, by a signal from a biosensor, or by any combination ofthese methods, as shown schematically in FIG. 3. First, a microprocessoris used in conjunction with a source of memory such as programmable readonly memory (PROM), a timer, a demultiplexer, and a power source such asa microbattery, such as is described, for example, by Jones et al.(1995) and Bates et al. (1992). The release pattern is written directlyinto the PROM by the user. The PROM sends these instructions to themicroprocessor. When the time for release has been reached as indicatedby the timer, the microprocessor sends a signal corresponding to theaddress (location) of a particular reservoir to the demultiplexer. Thedemultiplexer sends an input, such as an electric potential, to thereservoir addressed by the microprocessor. A microbattery provides thepower to operate the PROM, timer, and microprocessor, and provides theelectric potential input that is directed to a particular reservoir bythe demultiplexer. The manufacture, size, and location of each of thesecomponents is dependent upon the requirements of a particularapplication. In a preferred embodiment, the memory, timer,microprocessor, and demultiplexer circuitry is integrated directly ontothe surface of the chip. The microbattery is attached to the other sideof the chip and is connected to the device circuitry by vias or thinwires. However, in some cases, it is possible to use separate,prefabricated, component chips for memory, timing, processing, anddemultiplexing. These are attached to the backside of the miniaturizeddelivery device with the battery. The size and type of prefabricatedchips used depends on the overall dimensions of the delivery device andthe number of reservoirs. Second, activation of a particular reservoirby the application of an electric potential can be controlled externallyby remote control. Much of the circuitry used for remote control is thesame as that used in the preprogrammed method. The main difference isthat the PROM is replaced by a signal receiver. A signal such as radiowaves, microwaves, low power laser, or ultrasound is sent to thereceiver by an external source, for example, computers or ultrasoundgenerators. The signal is sent to the microprocessor where it istranslated into a reservoir address. Power is then directed through thedemultiplexer to the reservoir having the appropriate address. Third, abiosensor is integrated into the microchip to detect molecules in thesurrounding fluids. When the concentration of the molecules reaches acertain level, the sensor sends a signal to the microprocessor toactivate one or more reservoirs. The microprocessor directs powerthrough the demultiplexer to the particular reservoir(s).

[0062] G. Electric Potential Control Methods

[0063] The reservoir caps of an active device are anodes that oxidize toform soluble compounds and ions when a potential is applied between theanode and a cathode. For a given electrode material and electrolyte,there exists a range of electric potentials over which these oxidationreactions are thermodynamically and kinetically favorable. In order toreproducibly oxidize and open the reservoir caps of the device, theanode potential must be maintained within this favorable potentialrange.

[0064] There exist two primary control methods for maintaining anelectrode within a specific potential range. The first method is calledpotentiostatic control. As the name indicates, the potential is keptconstant during reservoir activation. Control of the potential istypically accomplished by incorporating a third electrode into thesystem that has a known, constant potential, called a referenceelectrode. The reference electrode can take the form of an externalprobe whose tip is placed within one to three millimeters of the anodesurface. The potential of the anode is measured and controlled withrespect to the known potential of a reference electrode such as asaturated calomel electrode (SCE). In a preferred embodiment ofpotentiostatic control, a thin film reference electrode and potentialfeedback controller circuitry could be fabricated directly onto thesurface of the microchip. For example, a microfabricated Ag/AgClreference electrode integrated with a microchip device would enable thedevice to maintain the anode potential of an activated reservoir withinthe oxidation regime until the reservoir was completely opened. Thesecond method is called galvanostatic control. As the name indicates,the current is kept constant during reservoir activation. One drawbackto this method of control is that there is more than one stablepotential for a given current density. However, if the current densityversus potential behavior is well characterized for the microchip devicein a particular electrolyte system, the current density that willmaintain the anode in the oxidation regime will be known. In this case,the galvanostatic method of potential control would be preferable to thepotentiostatic control, because galvanostatic control does not require areference electrode.

[0065] III. Applications for the Microchip Devices

[0066] Passive and active microchip devices have numerous in vitro andin vivo applications. The microchip can be used in vitro to deliversmall, controlled amounts of chemical reagents or other molecules tosolutions or reaction mixtures at precisely controlled times and rates.Analytical chemistry and medical diagnostics are examples of fieldswhere the microchip delivery device can be used. The microchip can beused in vivo as a drug delivery device. The microchips can be implantedinto a patient, either by surgical techniques or by injection, or can beswallowed. The microchips provide delivery of drugs to animals orpersons who are unable to remember or be ambulatory enough to takemedication. The microchips further provide delivery of many differentdrugs at varying rates and at varying times of delivery.

[0067] In a preferred embodiment, the reservoir cap enables passivetimed release, not requiring a power source, of molecules. Thereservoirs are capped with materials that degrade or dissolve at a knownrate or have a known permeability (diffusion constant) for the moleculesto be delivered. Therefore, the degradation, dissolution or diffusioncharacteristics of the cap material determine the time at which therelease of molecules in a particular reservoir begins. In effect, themicrochip provides dual control of the release of molecules by selectionof the release system (rate controller) and selection of the capmaterial (time controller, and in some cases, rate controller).

[0068] In another preferred embodiment, the reservoir cap enables activetimed release, requiring a power source, of molecules. In thisembodiment, the reservoir caps consist of a thin film of conductivematerial that is deposited over the reservoir, patterned to a desiredgeometry, and serves as an anode. Cathodes are also fabricated on thedevice with their size and placement dependent on the device'sapplication and method of electric potential control. Conductivematerials capable of dissolving into solution or forming solublecompounds or ions upon the application of an electric potential,including metals such as copper, gold, silver, and zinc and somepolymers, are used in the active timed release device. When an electricpotential is applied between an anode and cathode, the conductivematerial of the anode above the reservoir oxidizes to form solublecompounds or ions that dissolve into solution, exposing the releasesystem containing the molecules to be delivered to the surroundingfluids. Alternatively, the application of an electric potential can beused to create changes in local pH near the anode reservoir cap to allownormally insoluble ions or oxidation products to become soluble. Thiswould allow the reservoir to dissolve and expose the release system tothe surrounding fluids. In either case, the molecules to be deliveredare released into the surrounding fluids by diffusion out of or bydegradation or dissolution of the release system. The frequency ofrelease is controlled by incorporation of a miniaturized power sourceand microprocessor onto the microchip. Activation of any reservoir canbe achieved by preprogramming the microprocessor, by remote control, orby a signal from a biosensor.

[0069] The microchip devices and methods of fabrication thereof will befurther understood by reference to the following non-limiting examples.

Example 1 Fabrication of Active Release Microchip

[0070] 1) Obtain double side polished, prime grade, (100) orientedsilicon wafers.

[0071] Wafer thickness=approximately 295-310 μm

[0072] 2) Deposit approximately 1600-1900 Å of low stress (10:1, siliconrich) silicon nitride on both sides of the wafers in an SVG/Thermco 7000Series vertical tube reactor (VTR).

[0073] Gas Flows: Ammonia (NH₃)=24 sccm

[0074] Dichlorosilane (SiH₂Cl₂)=253 sccm

[0075] Temperature=780° C.

[0076] Chamber Pressure=268 mtorr

[0077] Deposition Rate=approximately 30 Å/min.

[0078] 3) Pattern positive photoresist (PR) as squares (approximately500 μm by 500 μm) serving as the large reservoir openings on one side ofthe wafers having low stress silicon nitride deposited on them.

[0079] Hexamethyldisilazane deposition on both sides of the wafer (“HMDSvapor prime”) in vacuum oven approximately 30 min. at 150° C.

[0080] Photoresist (PR) Type—OCG825-20

[0081] PR Spin Speed and Times (for a Solitec Inc. Model 5110 spinner)

[0082] 7 sec. at 500 rpm (coat)

[0083] 7 sec. at 750 rpm (spread)

[0084] 30 sec. at 3500 rpm (spin)

[0085] Prebake (in Blue M Model DDC-146C oven)

[0086] 30 min. at 90° C.

[0087] Ultraviolet (UV) exposure for each wafer in the contact aligner(Karl Suss Model MA4) with patterned mask

[0088] 32 sec. at wavelength=320 nm

[0089] Developer Type—OCG934 1:1

[0090] Put exposed wafers into slightly agitated, room temperaturedeveloper

[0091] Develop Time=approximately 40 seconds

[0092] Cascade Rinse=2 min.

[0093] Rinse and Dry Wafers in Spin Rinse Dryer (SRD)

[0094] Postbake (in Blue M Model DDC-146C oven)

[0095] 30 min. at 120° C.

[0096] 4) Etch the VTR nitride to the underlying silicon using a plasmaetcher (Plasmaquest Series II Reactor Model 145).

[0097] Gas Flows: Oxygen (O₂)=2 sccm

[0098] Helium (He)=15 sccm

[0099] Carbon Tetrafluoride (CF₄)=15 sccm

[0100] Power: RF=10 W

[0101] ECR=100 W

[0102] Chamber Pressure=20 mtorr

[0103] Temperature=25° C.

[0104] Nitride Etch Rate=approximately 350 Å/min

[0105] 5) Remove excess PR with solvents—acetone, methanol, isopropanol.

[0106] 6) Etch the exposed silicon in aqueous potassium hydroxide (KOH)in a wet processing hood (by Semifab, Inc.).

[0107] Concentration=approximately 38-40% by weight

[0108] Temperature=approximately 85-90° C.

[0109] Etch Rate=approximately 1 μm/min

[0110] 7) Post-KOH clean in a wet processing hood (by Laminaire Corp.)to avoid K⁺ contamination in cleanroom.

[0111] Piranha Clean for 15 min.

[0112] Dump Rinse=3 times

[0113] Hydrofluoric Acid (HF) Dip

[0114] 10 sec. in 50:1 water:HF solution (by volume)

[0115] Dump Rinse=3 times

[0116] Standard RCA clean

[0117] Rinse and Dry in SRD

[0118] 8) Pattern image reversal PR over the nitride membranes forsubsequent gold liftoff process.

[0119] HMDS vapor prime in vacuum oven

[0120] approximately 30 min. at 150° C.

[0121] Photoresist Type (PR)—AZ 5214 E

[0122] PR Spin Speed and Times (for a Solitec Inc. Model 5110 spinner)

[0123] 6 sec. at 500 rpm (coat)

[0124] 6 sec. at 750 rpm (spread)

[0125] 30 sec. at 4000 rpm (spin)

[0126] Prebake (in Blue M Model DDC-146C oven): 30 min. at 90° C.

[0127] Ultraviolet (UV) exposure for each wafer in the contact aligner(Karl Suss Model MA4) with patterned mask

[0128] 40 sec. at wavelength=320 nm

[0129] Bake for 90 sec. on a metal plate in an oven at 120° C. (Blue MModel DDC-146C)

[0130] UV flood exposure for each wafer in the contact aligner (KarlSuss Model MA4) WITHOUT a patterned mask (expose entire wafer)

[0131] Approximately 200 sec. at wavelength=320 nm

[0132] Developer Type—AZ 422 MIF

[0133] Put exposed wafers into slightly agitated, room temperaturedeveloper

[0134] Develop Time=approximately 1 min. 30 sec.

[0135] Cascade Rinse=2 min.

[0136] Rinse and Dry Wafers in Spin Rinse Dryer (SRD)

[0137] 9) Evaporation of gold onto the image reversal PR patterned sideof each wafer using a liftoff plate (wafer holder) in an electron beamevaporator (Temescal Semiconductor Products Model VES 2550).

[0138] Gold Deposition Rate=5 Å/sec.

[0139] Gold Thickness=approximately 3000 Å

[0140] Base Pressure=approximately 5.0×10⁻⁷ torr

[0141] Room Temperature (no outside heating or cooling)

[0142] 10) Liftoff gold layer with acetone.

[0143] 11) Clean wafers with solvents—acetone, methanol, isopropanol.

[0144] 12) Oxygen plasma clean (ash) in a plasma etcher (PlasmaquestSeries II Reactor Model 145).

[0145] Gas Flows: O₂=25 sccm

[0146] He=15 sccm

[0147] Power: RF=10 W

[0148] ECR=200 W

[0149] Chamber Pressure=20 mtorr

[0150] Temperature=25° C.

[0151] 13) Deposit plasma-enhanced chemical vapor deposition (PECVD)silicon dioxide over the entire surface of the wafers having the goldelectrodes on them using a PECVD chamber (Plasma-Therm 700 SeriesWaf'r/Batch Dual Chamber Plasma Processing System).

[0152] Gas Flows: 2% SiH₄ in N₂=400 sccm

[0153] N₂O=900 sccm

[0154] RF Power=20 W

[0155] Chamber Pressure=900 mtorr

[0156] Deposition Rate=approximately 250-500 Å/min.

[0157] Temperature=350° C.

[0158] 14) Clean wafers with solvents—acetone, methanol, isopropanol.

[0159] 15) Pattern PR to expose portions of the silicon dioxide coveringparts of the gold electrodes.

[0160] HMDS vapor prime in vacuum oven

[0161] approximately 30 min. at 150° C.

[0162] Photoresist (PR) Type—OCG825-20

[0163] PR Spin Speed and Times (for a Solitec Inc. Model 5110 spinner)

[0164] 7 sec. at 500 rpm (coat)

[0165] 7 sec. at 750 rpm (spread)

[0166] 30 sec. at 3500 rpm (spin)

[0167] Prebake (in Blue M Model DDC-146C oven): 30 min. at 90° C.

[0168] Ultraviolet (UV) exposure for each wafer in the contact aligner(Karl Suss Model MA4) with patterned mask

[0169] 32 sec. at wavelength=320 nm

[0170] Developer Type—OCG934 1:1

[0171] Put exposed wafers into slightly agitated, room temperaturedeveloper

[0172] Develop Time=approximately 55 seconds

[0173] Cascade Rinse=2 min.

[0174] Rinse and Dry Wafers in Spin Rinse Dryer (SRD)

[0175] Postbake (in Blue M Model DDC-146C oven): 30 min. at 120° C.

[0176] 16) Etch the exposed silicon dioxide to the gold surface with aplasma etcher (Plasmaquest Series II Reactor Model 145).

[0177] Gas Flows: He=15 sccm

[0178] CF₄=15 sccm

[0179] Power: RF=10 W

[0180] ECR=100 W

[0181] Chamber Pressure=20 mtorr

[0182] Temperature=15° C.

[0183] Silicon Dioxide Etch Rate=approximately 215 Å/min.

[0184] 17) Spin photoresist on the side of the wafers having the goldelectrodes to protect the electrodes during wafer dicing.

[0185] Photoresist (PR) Type—OCG825-20

[0186] PR Spin Speed and Times (for a Solitec Inc. Model 5110 spinner)

[0187] 7 sec. at 500 rpm (coat)

[0188] 7 sec. at 750 rpm (spread)

[0189] 30 sec. at 3500 rpm (spin)

[0190] Prebake (in Blue M Model DDC-146C oven): 30 min. at 90° C.

[0191] 18) Dice the wafers with a diesaw (Disco Automatic Dicing SawModel DAD-2H/6T).

[0192] Process yields 21 devices per 4″ wafer with each device measuring17 mm by 17 mm on a side

[0193] 19) Etch the nitride membrane from the back of the devices with aplasma etcher (Plasmaquest Series II Reactor Model 145).

[0194] Gas Flows: O₂=2 sccm

[0195] He=15 sccm

[0196] CF₄=15 sccm

[0197] Power: RF=10 W

[0198] ECR=100 W

[0199] Chamber Pressure=20 mtorr

[0200] Temperature=25° C.

[0201] Nitride Etch Rate=approximately 350 Å/min.

[0202] 20) Clean the devices with solvents and O₂ plasma.

[0203] Solvent clean—acetone, methanol, isopropanol

[0204] Oxygen plasma clean with a plasma etcher (Plasmaquest Series IIReactor Model 145)

[0205] Gas Flows: O₂=25 sccm

[0206] He=15 sccm

[0207] Power: RF=10 W

[0208] ECR=200 W

[0209] Chamber Pressure=20 mtorr

[0210] Temperature=25° C.

[0211] Fabrication of active microchip devices is complete.

Example 2 Fabrication of Passive Release Microchip

[0212] 1) Obtain double side polished, prime grade, (100) orientedsilicon wafers for devices having reservoirs extending completelythrough the wafer or single side polished, prime grade, (100) orientedsilicon wafers for devices having reservoirs that do not extendcompletely through the wafer.

[0213] Wafer thickness=approximately 295-310 μm for devices withreservoirs extending completely through the wafer (devices that do nothave reservoirs extending all the way through the wafer can be of anydesired thickness)

[0214] 2) Deposit approximately 1600-1900 Å of low stress (10:1, siliconrich) silicon nitride on both sides of the wafers in an SVG/Thermco 7000Series vertical tube reactor (VTR).

[0215] Gas Flows: Ammonia (NH₃)=24 sccm

[0216] Dichlorosilane (SiH₂Cl₂)=253 sccm

[0217] Temperature=780° C.

[0218] Chamber Pressure=268 mtorr

[0219] Deposition Rate=approximately 30 Å/min.

[0220] 3) Pattern positive PR as squares (approximately 500 μm by 500 μmfor devices with reservoirs extending completely through the wafer orany desired dimension for devices that do not have reservoirs extendingall the way through the wafer) serving as the large reservoir openingson one side of the wafers having low stress silicon nitride deposited onthem.

[0221] Hexamethyldisilazane deposition on both sides of the wafer (“HMDSvapor prime”) in vacuum oven approximately 30 min. at 150° C.

[0222] Photoresist (PR) Type—OCG825-20

[0223] PR Spin Speed and Times (for a Solitec Inc. Model 5110 spinner)

[0224] 7 sec. at 500 rpm (coat)

[0225] 7 sec. at 750 rpm (spread)

[0226] 30 sec. at 3500 rpm (spin)

[0227] Prebake (in Blue M Model DDC-146C oven)

[0228] 30 min. at 90° C.

[0229] Ultraviolet (UV) exposure for each wafer in the contact aligner(Karl Suss Model MA4) with patterned mask

[0230] 32 sec. at wavelength=320 nm

[0231] Developer Type—OCG934 1:1

[0232] Put exposed wafers into slightly agitated, room temperaturedeveloper

[0233] Develop Time=approximately 40 seconds

[0234] Cascade Rinse=2 min.

[0235] Rinse and Dry Wafers in Spin Rinse Dryer (SRD)

[0236] Postbake (in Blue M Model DDC-146C oven): 30 min. at 120° C.

[0237] 4) Etch the VTR nitride to the underlying silicon using a plasmaetcher (Plasmaquest Series II Reactor Model 145).

[0238] Gas Flows: Oxygen (O₂)=2 sccm

[0239] Helium (He)=15 sccm

[0240] Carbon Tetrafluoride (CF₄)=15 sccm

[0241] Power: RF=10 W

[0242] ECR=100 W

[0243] Chamber Pressure=20 mtorr

[0244] Temperature=25° C.

[0245] Nitride Etch Rate=approximately 350 Å/min.

[0246] 5) Remove excess PR with solvents—acetone, methanol, isopropanol.

[0247] 6) Etch the exposed silicon in aqueous potassium hydroxide (KOH)in a wet processing hood (by Semifab, Inc.).

[0248] Concentration=approximately 38-40% by weight

[0249] Temperature=approximately 85-90° C.

[0250] Etch Rate=approximately 1 μm/min.

[0251] 7) Post-KOH clean in a wet processing hood (by Laminaire Corp.)to avoid K⁺ contamination in cleanroom.

[0252] Piranha Clean for 15 min.

[0253] Dump Rinse=3 times

[0254] Hydrofluoric Acid (HF) Dip

[0255] 10 sec. in 50:1 water:HF solution (by volume)

[0256] Dump Rinse=3 times

[0257] Standard RCA clean

[0258] Rinse and Dry in SRD

[0259] For those devices not having a nitride membrane (reservoirs notextending completely through the wafer), fabrication of passivemicrochip device is complete. Dice the wafer into individual devices.The reservoirs of each device are ready to be filled.

[0260] Alternately, for those devices having a nitride membrane(reservoirs extend completely through the wafer), continue with thefollowing steps.

[0261] 8) Fill the reservoir using injection, inkjet printing, spincoating or another method with reservoir cap materials, release system,and molecules to be released, or any combination thereof.

[0262] 9) Seal the reservoir openings on the side of the wafer throughwhich the reservoirs were filled.

[0263] 10) Etch the nitride membranes on the side of the wafer oppositethe filling side by using a plasma etcher (Plasmaquest Series II ReactorModel 145) until the cap material or release system is reached (etchparameters may vary depending on the type of cap material or releasesystem under the nitride).

[0264] Gas Flows: Oxygen (O₂)=2 sccm

[0265] Helium (He)=15 sccm

[0266] Carbon Tetrafluoride (CF₄)=15 sccm

[0267] Power: RF=10 W

[0268] ECR=100 W

[0269] Chamber Pressure=20 mtorr

[0270] Temperature=25° C.

[0271] Nitride Etch Rate=approximately 350 Å/min.

[0272] 11) Spin photoresist on the side of the wafers having exposed capmaterials or release system to protect them during wafer dicing (thisstep may not be necessary, depending on the type of exposed cap materialor release system).

[0273] Photoresist (PR) Type—OCG825-20

[0274] PR Spin Speed and Times (for a Solitec Inc. Model 5110 spinner)

[0275] 7 sec. at 500 rpm (coat)

[0276] 7 sec. at 750 rpm (spread)

[0277] 30 sec. at 3500 rpm (spin)

[0278] Prebake (in Blue M Model DDC-146C oven): 30 min. at 90° C.

[0279] 12) Dice the wafers with a diesaw (Disco Automatic Dicing SawModel DAD-2H/6T).

[0280] Process yields 21 devices per 4″ wafer with each device measuring17 mm by 17 mm on a side

[0281] 13) Clean the devices with solvents and O₂ plasma (these stepsmay not be necessary, depending on the type of exposed cap material orrelease system).

[0282] Solvent clean—acetone, methanol, isopropanol

[0283] Oxygen plasma clean in a plasma etcher (Plasmaquest Series IIReactor Model 145)

[0284] Gas Flows: O₂=25 sccm

[0285] He=15 sccm

[0286] Power: RF=10 W

[0287] ECR=200 W

[0288] Chamber Pressure=20 mtorr

[0289] Temperature=25° C.

[0290] Fabrication of passive microchip device is complete.

Example 3 Microchip with Passive Timed Drug Release

[0291] A passive timed release device, microchip 10 is shown in FIG. 4.Microchip 10 is formed from substrate 14. Reservoirs 16 are etched intosubstrate 14. Positioned in reservoirs 16 is a release system containingmolecules for delivery 18. The reservoirs are capped with reservoir caps12. The release system and the molecules for delivery 18 can varybetween rows 20 a, 20 b, 20 c, and within reservoirs of each row.

[0292] Microchip 10 can be inserted into solution for in vitroapplications or be implanted in a selected part of the body for in vivoapplications and left to operate without requiring further attention.When exposed to the surrounding fluids, reservoir caps 12 will degradeor become permeable to the release system containing molecules fordelivery 18.

Example 4 Microchip With Active Controlled Time Release

[0293] A drug delivery device that provides active timed release isshown as microchip 100 in FIG. 5. Microchip 100 is similar to microchip10 except that microchip 100 contains electrodes that provide for activetimed release. Microchip 100 is formed from substrate 160, releasesystem containing molecules for delivery 180, anode reservoir caps 120,and cathodes 140. Preferably, microchip 100 further includes an inputsource, a microprocessor, a timer, a demultiplexer, and a power source(not shown). The power source provides energy to drive the reactionbetween selected anodes and cathodes. Upon application of a smallpotential between the electrodes, electrons pass from the anode to thecathode through the external circuit causing the anode material tooxidize and dissolve into the surrounding fluids, exposing the releasesystem containing the molecules for delivery 180 to the surroundingfluids. The microprocessor directs power to specific electrode pairsthrough a demultiplexer as directed by a PROM, remote control, orbiosensor.

[0294] Another drug delivery device that provides active timed releaseis shown as microchip 200 in FIG. 6. Microchip 200, which includessubstrate 260 and release system containing molecules 280 for delivery,is similar to microchip 100, but includes different electrodeconfigurations. Microchip 200 illustrates that the shape, size, ratio,and placement of the anodes and cathodes can vary.

Example 5 Microchip Device Having Multi-Portion Substrate

[0295]FIGS. 9a-e illustrate several typical variations of the deviceswherein two or more substrate portions are attached to one another toform, for example, a larger or composite substrate. The reservoir capsare shown generically, that is, insulator/etch mask materials, insulatoroverlayer materials, and anode/cathode materials are omitted from theseFigures, except where a specific embodiment is otherwise indicated.These devices can provide active release, passive release, or acombination thereof.

[0296]FIG. 9a, for comparison, shows a “single” substrate device 500,which has substrate 510, in which reservoirs 520 are filled withmolecules to be released 540. Reservoirs 520 are covered by reservoircaps 530 and sealed with backing plate 550 or other type of seal.

[0297]FIG. 9b shows device 600 having a substrate formed of a topsubstrate portion 610 a bonded to bottom substrate portion 610 b.Reservoirs 620 a, in top substrate portion 610 a are in communicationwith reservoirs 620 b in bottom substrate portion 610 b. Reservoirs 620a/620 b are filled with molecules to be released 640 and are covered byreservoir caps 630 and sealed with backing plate 650 or other type ofseal.

[0298]FIG. 9c shows device 700 having a substrate formed of a topsubstrate portion 710 a bonded to bottom substrate portion 710 b. Topsubstrate portion 710 a has reservoir 720 a which is in communicationwith reservoir 720 b in bottom substrate portion 710 b. Reservoir 720 bis much larger than reservoir 720 a and reservoirs 720 a/720 b containmolecules to be released 740. Reservoirs 720 a/720 b are filled withmolecules to be released 740 and are covered by reservoir cap 730 andsealed with backing plate 750 or other type of seal.

[0299]FIG. 9d shows device 800 having a substrate formed of a topsubstrate portion 810 a bonded to bottom substrate portion 810 b. Topsubstrate portion 810 a has reservoir 820 a which contains firstmolecules to be released 840 a. Bottom substrate portion 810 b hasreservoir 820 b which contains second molecules to be released 840 b.First molecules to be released 840 a can be the same or different fromsecond molecules to be released 840 b. Reservoir 820 a is covered byreservoir cap 830 a and sealed by reservoir cap 830 b (formed of ananode material) and partially by bottom substrate portion 810 b.Reservoir 820 b is covered by internal reservoir cap 830 b and sealedwith backing plate 850 or other type of seal. Cathodes 860 a and 860 bare positioned to form an electric potential with anode reservoir cap830 b.

[0300] In one embodiment of the device shown in FIG. 9d, secondmolecules to be released 840 b are first released from reservoir 820 b,through or following the disintegration of reservoir cap 830 b, intoreservoir 820 a, wherein the second molecules mix with first moleculesto be released 840 a before the mixture of molecules is released fromreservoir 820 a through or following the disintegration of reservoir cap830 a.

[0301]FIG. 9e simply shows another reservoir shape configuration incross-section. Substrate portions 610 a/710 a/810 a can be formed fromthe same or different materials and can have the same or differentthicknesses as substrate portions 610 b/710 b/810 b. These substrateportions can be bonded or attached together (as described in section IIAabove) after they have been individually processed (e.g., etched), orthey may be formed before they have any reservoirs or other featuresetched or micro-machined into them (such as in SOI substrates).

[0302] Modifications and variations of the methods and devices describedherein will be obvious to those skilled in the art from the foregoingdetailed description. Such modifications and variations are intended tocome within the scope of the appended claims.

We claim:
 1. An implantable medical device for the controlled release ofdrug molecules comprising: a support structure; at least two discretereservoirs provided in spaced positions across at least one surface ofthe support structure; and a release system loaded in each of the atleast two reservoirs, the release system including drug moleculesdispersed in a degradable matrix material, wherein rate of release ofthe drug molecules from the reservoir is controlled by the matrixmaterial.
 2. The implantable medical device of claim 1, wherein therelease of the drug molecules from the reservoirs is controlled by thein vivo disintegration of the matrix material.
 3. The implantablemedical device of claim 2, wherein the disintegration of the degradablematrix material is by dissolution, enzymatic hydrolysis, or erosion. 4.The implantable medical device of claim 1, wherein the matrix materialcomprises one or more hydrogels or biodegradable polymers.
 5. Theimplantable medical device of claim 4, wherein said one or morebiodegradable polymers are selected from the group consisting ofpoly(amides), poly(esters), poly(anhydrides), poly(orthoesters),poly(carbonates), copolymers thereof, and mixtures thereof.
 6. Theimplantable medical device of claim 4, wherein said one or morebiodegradable polymers are selected from the group consisting ofpoly(lactic acids), poly(glycolic acids), poly(lactic-co-glycolicacids), poly(caprolactones), and mixtures thereof
 7. The implantablemedical device of claim 1, wherein the drug molecules areheterogeneously dispersed within each reservoir.
 8. The implantablemedical device of claim 1, wherein the drug molecules are homogeneouslydispersed within each reservoir.
 9. The implantable medical device ofclaim 1, wherein the drug molecules comprise one or more therapeuticagents selected from the group consisting of anesthetics,chemotherapeutic agents, hormones, immunomodulators, ion channelregulators, and antibiotics.
 10. The implantable medical device of claim1, wherein the dose of drug molecules in one of the at least tworeservoirs is different from the dose of drug molecules in the other ofthe at least two reservoirs.
 11. The implantable medical device of claim1, wherein the kinetics of release of the drug molecules from one of theat least two reservoirs is different from the kinetics of release of thedrug molecules from the other of the at least two reservoirs.
 12. Theimplantable medical device of claim 1, wherein a first drug is in one ofthe at least two reservoirs and a second, different drug is in the otherof the at least two reservoirs.
 13. The implantable medical device ofclaim 1, wherein at least one of the reservoirs comprises two or morelayers of the release system.
 14. The implantable medical device ofclaim 13, wherein a first drug is contained in a first layer of the twoor more layers, and a second drug is contained in a second layer of thetwo or more layers.
 15. The implantable medical device of claim 1,wherein the at least two reservoirs each comprises at least two layersof a release system and at least one layer of a degradable or solublematerial which does not comprise the one or more drugs.
 16. Theimplantable medical device of claim 1, wherein the release systemfurther comprises one or more pharmaceutically acceptable carriers,excipients, or diluents.
 17. The implantable medical device of claim 1,further comprising at least two discrete biodegradable reservoir caps,each reservoir cap covering one of the at least two reservoir, andcontrolling the time of release of the drug molecules from thereservoirs.
 18. The implantable medical device of claim 17, wherein oneof the reservoir caps is formed of a first material and the other of theat least two reservoir caps is formed of a second material, wherein thefirst material has a different disintegration rate in vivo compared tothe second material.
 19. The implantable medical device of claim 17,wherein one of the reservoir caps has a first thickness and the other ofthe at least two reservoir caps has a second, greater thickness.
 20. Theimplantable medical device of claim 17, wherein at least one of thereservoir caps comprises one or more synthetic polymers.
 21. Theimplantable medical device of claim 1, which provides pulsatile releaseof the one or more drugs.
 22. The implantable medical device of claim 1,comprising at least two rows of the at least two reservoirs in an arrayin the implantable device.
 23. The implantable medical device of claim22, wherein a first release system is in each of the at least tworeservoirs of a first of the at least two rows and a second releasesystem is in each of the at least two reservoirs of the other of the atleast two rows, the first release system releasing the one or more drugsat a rate or in a dosage amount different from release of the one ormore drugs from the second release system.
 24. An implantable medicaldevice for the controlled release of drug molecules comprising: asupport structure; at least two discrete reservoirs provided in spacedpositions across at least one surface of the support structure; and arelease system loaded in each of the at least two reservoirs, therelease system including drug molecules dispersed in a non-degradablematrix material, wherein rate of release of the drug molecules from thereservoir is controlled by the matrix material.
 25. The implantablemedical device of claim 24, wherein release of the drug molecules fromthe reservoir is controlled by in vivo diffusion of the drug moleculesfrom the matrix material.
 26. The implantable medical device of claim24, wherein the matrix material comprises one or more hydrogels orsynthetic polymers.
 27. The implantable medical device of claim 26,wherein said one or more synthetic polymers are selected from the groupconsisting of poly(ethers), poly(acrylates), poly(methacrylates),poly(vinyl pyrolidones), poly(vinyl acetates), poly(urethanes),celluloses, cellulose acetates, and poly(siloxanes).
 28. The implantablemedical device of claim 24, wherein the drug molecules areheterogeneously dispersed within each reservoir.
 29. The implantablemedical device of claim 24, wherein the drug molecules comprise one ormore therapeutic agents selected from the group consisting ofanesthetics, chemotherapeutic agents, hormones, immunomodulators, ionchannel regulators, and antibiotics.
 30. The implantable medical deviceof claim 24, wherein the dose of drug molecules in one of the at leasttwo reservoirs is different from the dose of drug molecules in the otherof the at least two reservoirs.
 31. The implantable medical device ofclaim 24, wherein the kinetics of release of the drug molecules from oneof the at least two reservoirs is different from the kinetics of releaseof the drug molecules from the other of the at least two reservoirs. 32.The implantable medical device of claim 24, wherein a first drug is inone of the at least two reservoirs and a second, different drug is inthe other of the at least two reservoirs.
 33. The implantable medicaldevice of claim 24, wherein at least one of the reservoirs comprises twoor more layers of the release system.
 34. The implantable medical deviceof claim 33, wherein a first drug is contained in a first layer of thetwo or more layers, and a second drug is contained in a second layer ofthe two or more layers.
 35. The implantable medical device of claim 24,further comprising at least two discrete biodegradable reservoir caps,each reservoir cap covering one of the at least two reservoir andcontrolling the time of release of the drug molecules from thereservoirs.
 36. The implantable medical device of claim 35, wherein oneof the reservoir caps is formed of a first material and the other of theat least two reservoir caps is formed of a second material, wherein thefirst material has a different disintegration rate in vivo compared tothe second material.
 37. The implantable medical device of claim 35,wherein one of the reservoir caps has a first thickness and the other ofthe at least two reservoir caps has a second, greater thickness.
 38. Theimplantable medical device of claim 35, wherein at least one of thereservoir caps comprises one or more synthetic polymers.
 39. Theimplantable medical device of claim 24, further comprising at least twodiscrete non-degradable reservoir caps, each reservoir cap covering oneof the at least two reservoirs and further controlling the kinetics ofrelease of the drug molecules from the reservoirs.
 40. The implantablemedical device of claim 39, wherein at least one of the discretereservoir caps comprises one or more synthetic polymers.
 41. Theimplantable medical device of claim 24, comprising at least two rows ofthe at least two reservoirs in an array in the implantable device. 42.The implantable medical device of claim 41, wherein a first releasesystem is in each of the at least two reservoirs of a first row and asecond release system is in each of the at least two reservoirs of theother of the at least two rows, the first release system releasing theone or more drugs at a rate or in a dosage amount different from releaseof the one or more drugs from the second release system.
 43. A methodfor local delivery of drug molecules in a patient, the methodcomprising: implanting at a site in a patient a drug delivery devicewhich comprises a support structure, at least two discrete reservoirsprovided in spaced positions across at least one surface of the supportstructure, and a release system loaded in each of the reservoirs, therelease system including drug molecules dispersed in a degradable matrixmaterial; and allowing the matrix material to disintegrate in vivo torelease the drug molecules from the reservoirs to the site in acontrolled manner.
 44. The method of claim 43, wherein the drug deliverydevice is implanted via a catheter.
 45. The method of claim 43, whereinthe drug molecules are released from the device in a pulsatile manner.46. The method of claim 43, wherein the drug molecules are released fromthe device over a period of time of at least three months.
 47. Themethod of claim 43, wherein one of the at least two reservoirs comprisestwo or more layers of the release system.
 48. The method of claim 43,wherein the kinetics of release of the drug molecules from one of the atleast two reservoirs is different than the kinetics of release of thedrug molecules from the other of the at least two reservoirs.
 49. Themethod of claim 43, wherein the drug delivery device further comprisesat least two discrete degradable reservoir caps, each reservoir capcovering one of the at least two reservoirs and delaying onset ofrelease of the drug molecules therefrom.
 50. A method for local deliverydrug molecules in a patient, the method comprising: implanting at a sitein a patient a drug delivery device which comprises a support structure,at least two discrete reservoirs provided in spaced positions across atleast one surface of the support structure, and a release system loadedin each of the reservoirs, the release system including drug moleculesdispersed in a non-degradable matrix material; and allowing the drugmolecules to diffuse from the matrix material in vivo to release thedrug molecules from the reservoirs to the site in a controlled manner.51. The method of claim 50, wherein the drug delivery device isimplanted via a catheter.
 52. The method of claim 50, wherein the drugmolecules are released from the device over a period of time of at leastthree months.
 53. The method of claim 50, wherein the kinetics ofrelease of the drug molecules from one of the at least two reservoirs isdifferent than the kinetics of release of the drug molecules from theother of the at least two reservoirs.
 54. The method of claim 50,wherein the drug delivery device further comprises at least two discretereservoir caps, each reservoir cap covering one of the at least tworeservoirs and delaying the onset of release of the drug moleculestherefrom.